The Molecular Hematology Laboratory supports efforts by investigators from several institutes to improve the safety and efficacy of allogeneic stem cell grafts as a therapeutic modality for curing a variety of clinical diseases. Among other worthy efforts, three clinical initiatives merit particular notice. 1. Recent protocols initiated by principal investigator Dennis Hickstein from the NCI, use a modified conditioning protocol for HLA-matched allogeneic stem cell transplantation to reverse the immunodeficiency and myelodysplasia seen in patients with mutations in GATA2. This approach has also been adapted to treat patients with Dock8, another severe, often fatal, hereditary immunodeficiency disease. These studies rely heavily on the Molecular Hematology Laboratory to document successful engraftment and in patients who had already developed myelodysplasia or acute myelogenous leukemia at the time of transplantation, to detect early evidence of recurrence. 2. John Tisdale and Matthew Hsieh, Investigators from NIDDK continue refining their protocols for HLA-matched allogeneic stem cell transplantation to reverse hemoglobinopathy in patients with clinically advanced sickle cell anemia and other hemoglobinopathies. These studies employ a very gentle conditioning regimen to promote split chimerism i.e. extensive donor myeloid engraftment with minimal T cell donor engraftment. Using this approach they are able to reverse or markedly ameliorate hemoglobinopathy in extremely fragile patients with virtually no graft versus host disease or treatment related mortality. Our routine subset chimerism analyses are crucial to their efforts. 3. Richard Childs, an investigator from NHLBI has developed an innovative protocol for treating patients with severe aplastic anemia and no suitable HLA-matched donor. These patients receive a double transplant consisting of T-cell depleted, haploidentical parental myeloid cells and matched unselected cord blood cells from an unrelated HLA matched donor. The extent of haploidentical and cord blood engraftment varies substantially from patient to patient, but most transplanted patients have been dramatically benefited by the procedure. During the past year, we have undertaken extensive retrospective studies to measure the degree of donor chimerism in flow sorted derived T cells, B cells, and NK cells taken from patients at crucial points during engraftment. These studies still in progress may identify patterns of differential subset engraftment that help explain and predict the sometimes erratic course of engraftment in individual patients.